Diuretic agents are a class of drugs that increase urine production, thereby leading to increased urine volume. There are several different types of diuretics that act in distinct ways. The main types are osmotic diuretics (eg mannitol), high ceiling diuretics such as furosemide, bumetanide, ethacrynic acid and torsemide (also known as loop diuretics), thiazides (eg hydrochlorothiazide), carbonic anhydrase inhibitors (eg acetazolamide), and potassium-sparing diuretics (eg aldosterone antagonists such as spironolactone, and epithelial sodium channel blockers such as amiloride). Diuretic agents are used in the treatment and/or prevention of a wide variety of diseases and medical conditions including, for example, liver cirrhosis, ascites associated with liver cirrhosis, diabetes insipidus, glaucoma, and renal diseases and conditions such as nephrotic syndrome, hypercalcemia, contrast-induced nephropathy (CIN), chronic kidney disease (CKD) (including CKD in patients on dialysis) and acute renal failure (ARF) (as may be associated with cardiovascular operations, severe traumatic injury and haemolytic transfusion reactions) which is otherwise known as acute kidney injury (AKI). However, the greatest use of diuretic agents resides in the treatment of oedema associated with hypertension, cardio-renal syndrome (CRS) and congestive heart failure (both chronic congestive heart failure (CHF) and acute decompensated congestive heart failure (ADCHF; also abbreviated to ADHF)).
Indeed, the administration of diuretic agents is a critical component of the typical treatments or “standard of care” (SOC) treatments of CHF patients, and in many cases, such treatments comprise the long term use of diuretic agents (usually a loop diuretic). Generally, the aim of these treatments is to achieve an increase in urine output and weight reduction of 0.5 to 1.0 kg daily (Heart Foundation Guidelines, October 2011), at which time the dosage of the diuretic agent ought to be reduced (albeit with ongoing regular reassessment and dosage adjustment according to volume status, if necessary). However, even with dosage reduction, long term use of diuretic agents may be undesirable or cause complications. For instance, during treatment with loop diuretics, patients should be monitored for hypokalaemia (a condition wherein there are abnormally low amounts of potassium in the blood which can lead to a range of symptoms and other undesirable outcomes including cardiac arrhythmias, constipation, and muscle weakness, myalgia and cramps (Heart Foundation Guidelines, October 2011)). The use of the loop diuretic furosemide has been described as “entrenched in today's suggested standard of care for chronic cardiac failure” (Weber, 2004). Integral to the safe long term use of this agent in CHF patients is the regular monitoring of serum electrolytes to manage, not only for incidents or risk of hypokalaemia, but also hypomagnesemia (a condition characterised by low amounts of magnesium in the blood and capable of causing symptoms such as cardiac arrhythmias and tachycardia, hypertension, muscle weakness and cramps, tremors, confusion and depression), and hypercalcemia (a condition characterised by an abnormally high blood concentration of calcium and capable of causing symptoms such as fatigue, bone pain, abdominal pain, muscle weakness, vomiting and constipation). In addition, furosemide can lead to a thiamine deficiency (Weber 2004), which if left untreated (eg by supplemental dietary thiamine) may cause symptoms of fatigue, irritability, depression and abdominal discomfort. Furosemide use has also been linked to hyperglycaemia and the development of gout caused by hyperuricemia. Moreover, it has been recognised that with oral administration (generally the desired mode for long term, at home use of drug agents) of diuretic agents, a “vicious cycle” can develop where the deteriorating clinical status of the patient contributes to gut wall oedema which, in turn, can cause reduced absorption of the diuretic agent, less effective fluid loss and, consequently, further deterioration in the patient's condition (Heart Foundation Guidelines, October 2011).
Since SOC treatments of CHF patients critically involves the administration of a diuretic agent, it is unremarkable that renal function is a key factor in predicting the risk of rehospitalisation and mortality in patients with CHF, as well as in limiting the management of patients with ADCHF. As such, patients with impaired cardiac and renal function are often described as a separate entity (ie as patients with cardio-renal syndrome, CRS), and provide a greater societal burden in terms of health care costs, morbidity and mortality. Given then that CHF/ADCHF patients commonly show diuretic resistance and that SOC treatments may, in some patients, actually lead to a reduced level of responsiveness to diuretic therapy (eg by the development of acute diuretic resistance or refractory diuretic responsiveness; Valente et al., 2014, and Voors et al., 2014), which is commonly addressed by simply increasing the dosage of the diuretic agent until a maximum effective dose is reached (ie. where there is no further diuresis achieved), treatments that target this patient population are specifically lacking and an unmet clinical need exists.
Thus, there is a desire in the art to avoid long term use of any one diuretic agent (such as furosemide) or, otherwise, at least reduce the dosage level(s) of the diuretic agent during such long term usage, as well as improve treatment options for CHF patients and ADCHF patients and, particularly in those patients showing impaired renal function.
The present applicant is developing novel therapies for, inter alia, CHF and ADCHF involving, in particular, the administration of vessel dilator (VSDL/VD). VSDL is a naturally occurring 37 amino acid cardiac peptide consisting of amino acids 31-67 of the 126 amino acid protein known as atrial natriuretic peptide (ANP) prohormone (proANP)(Vesely, 2002). The main biological activity of VSDL is to regulate blood pressure and maintain plasma volume in healthy individuals (Vesely, 2003). It is considered that VSDL offers a safe and potential effective treatment for conditions such as CHF and ADCHF by mediating beneficial haemodynamic effects through mechanisms of regulating plasma volume and blood pressure (BP) within clinically acceptable ranges and without seriously adverse side-effects (Vesely et al., 1994 and 1998). Indeed, in previous work (described in WO 2012/019237) using intravenous (iv) infusion of VSDL in patients showing either acute exacerbations of chronic CHF or ADCHF, the present applicant was able to achieve improved outcomes (eg increased cardiac index (CI), and drops in pulmonary capillary wedge pressure (PCWP) and blood pressure) without side-effects, even with very low doses of the peptide. However, it was hitherto considered that these beneficial haemodynamic effects are achieved primarily through vasodilatory activity. In further work described herein, it has been found that infusion of VSDL (along with SOC treatment) can achieve significant improvements in renal function and increased urine output associated with improvements in cardiac function, even in patients showing renal impairment (eg as shown by an estimated glomerular filtration rate (eGFR) of <75-90 ml/min/1.73 m2). As a consequence, it is considered that VSDL shows considerable promise as the basis of an adjuvant treatment to standard of care (SOC) diuretic treatment of CHF and/or ADCHF patients.